Identification of Neuromedin U as a sleep regulator

The first large scale screening in zebrafish helped biologists at the California Institute of Technology to identify a gene Neuromedin U (Nmu) which leads to severe insomnia when overactivated.

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Sleep is one of the most important factors governing our life. David Prober, the assistant professor of biology at Caltech said, “Sleep is a mysterious process. We spend a third of our lives doing it, and every animal with a complex nervous system seems to do it, so it must be important. But we still don’t understand why we do it or how it’s regulated.”

In order to identify the genetic basis of such behaviors, a genetic screening is the best experimental technique used. It is the method of choice for simpler organisms like fruit flies and involves mutating the DNA of the model organism, raising them and then identifying any observable change in the behavior followed by determination of the altered gene product that caused the change.

However, the zebrafish has recently emerged as a good vertebrate model system owing to its quick development, transparent embryonic and larval stages and anatomical and molecular similarities with the human brain.

A gain-of-function approach was used in the study. The single celled embryos were injected with a plasmid carrying genes of importance, specially those that encoded neuropeptides (protein-like molecules used by neurons for communication). A heat-shock promoter that turned on when the fish were heated to 37 degree Celsius allowed the over-expression of those genes. The genes which in particular affected sleep were identified using computerized video trackers and later on transgenic zebrafish were created that expressed each of those genes. Overexpression of Nmu was the most significant change observed in all those cells. Nmu is expressed in the hypothalamus (a structure that is responsible for sleep regulation) in mammals.

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Zebrafish wakes up at the end of night and turns active when the lights turn on. “After heat shock, the fish that overexpress Nmu are much more active both during the day and at night,” says Prober. “The fish almost don’t sleep at all the night following the heat shock—so they display a very profound form of insomnia. The fish without Nmu are defective in this anticipation of dawn, so it seems that this gene is particularly important for the transition from nighttime sleep to daytime wakefulness.”

They also investigated Nmu’s role in the hypothalamic-pituitary-adrenal (HPA) axis, a stress response pathway and observed that corticotrophin-releasing hormone (CRH) cells in the brain stem were activated by Nmu overexpression. Thus, the study revealed an unexpected relationship between the Nmu gene and the sleep/ wake states in vertebrates.